Subarachnoid hemorrhage consists of 50% of all stroke deaths in younger age groups in Japan, therefore, its prevention is an important issue. Recent refinement of MRA revealed that the incidence of unruptured cerebral aneurysms in healthy adults is more than 5%, and with family history of subarachnoid hemorrhage it is more than 10%. Because the overall risk of rupture is supposed to be about 1% per year, less than 0.5% when it is small, operative indication should be cautiously considered. In future, an effective screening targeting a high risk group, improvement of operative technique, follow-up of unoperated patients and statistical survery for the incidence of subarachnoid hemorrhage would be the works to be done.

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Surgeries have been taken an important role of treatment for hypertensive intracerebral hemorrhage. But operative indication is not firmly established on each location of the hematoma and the method of the surgery as craniotomy vs stereotaxic aspiration is also controversial topics. In this article, operative indication of putaminal hemorrhage is considered from a viewpoint of functional outcome such as recovery of motor function in the mild case and of consciousness disturbance in the severe case. Pathophysiological conditions after bleeding, which include rebleeding, hydrocephalus and brain edema, are also menitoned in relation to surgical treatment.

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We studied the relationship between silent brain infarction (SBI) and hypertension in stroke-free subjects who visited to brain check-up. The subjects with SBI showed significantly higher incidence of hypertension history, and higher blood pressure at brain check-up and at home than those without SBI. Duration of hypertension, daily blood pressure (BP), BP at brain check-up and condition of taking antihypertensive drugs did not relate to SBI in hypertensive subjects. In prospective study, higher incidence of stroke onset was observed in the subjects who showed higher BP at brain check-up and in hypertensives with SBI than those without. Hypertensives with family history of stroke showed significantly greater incidence of stroke onset than those without. These results indicate that not only hypertension but some genetic factors may contribute to stroke onset from SBI.

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The purpose of this study was to diagnose the acute stroke by diffusion weighted imaging (DWI) and perfusion image (PI) using echo planar imaging (EPI).
Ten cases of acute stroke within 12 hours after onset were imaged with FLAIR, DWI and PI. All imaging was performed using a 1.5 T Signa Horizon MRI scanner (GE-YMS). The imaging parameters of the DWI were employed in four times, namely b=250, 500, 750, 1000 sec/. PI was performed with single shot gradient echo type echo-planar technique during the injection of 0.2 mmol per kilogram of body weight gadopentate dimeglumine, TR/TE=333 ms/55 ms, matrix=128×1 NEX, thickness 5 mm, FOV 24 cm. Apparent diffusion coefficient (ADC) map, relative cerebral blood volume (rCBV) map, and relative mean transit time (rMTT) map were reconstructed by workstation. Measurement of ADC, MTT ratio and CBV ratio in ischemic core and peripheral region were evaluated respectively and compared with follow up imaging in over 1 month after onset.
(1) ADC value were reduced to 45.2% and 78.2% in the ischemic core and penumbra respectively. (2) rCBV ratio and rMTT ratio were 32% and 148% in the ischemic core, 73% and 167% in the peripheral region, respectively. (3) Perfusion map can be classified into 4 types according to the grade of ischemia.
ADC and perfusion map can demonstrate the grade of ischemia in acute stage.

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We studied diffusion-weighted magnetic resonance imaging (DWI) and single photon emission computed tomography (SPECT) in 14 patients with unilateral intracranial steno-occlusive arterial lesion to evaluate the relationship between the apparent diffusion of coefficient (ADC) of water and cerebral blood flow (CBF) in the acute stage of human cerebral infarction. In all patients DWI and SPECT measurements were performed within 6 hours after onset of stroke, and relative ADC (rADC) and relative CBF (rCBF) of the infarct and peri-infarct areas were calculated with referring to the follow-up computed tomography (CT) obtained more than 24 hours after onset. The rADC significantly correlated with rCBF (P<0.01). In the area with moderate and severe hypoperfusion, rADC of the infarct areas significantly decreased compared with unity (p<0.01). Standard deviation of the infarct area was greater than that of the periinfarct area, and 2 lesions with normal rADC and moderate hypoperfusion later evolved into complete infarction. The present results demonstrate that the ADC reduction of the ischemic area correlates with the severity of hypoperfusion within 6 hours after stroke onset. Normal ADC, however, is not a token of escaping form cerbral infarction when moderate hypoperfusion is associated.

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Evolution of ischemic lesion volume in echo-planar diffusion weighted MRI (EP-DWI) was investigat-ed in 17 patients with acute ischemic stroke. Comparing to the follow-up MRI studies, lesion volume expansion up to 317 ml was observed in patients whose initial EP-DWI performed within 17 hours after the onset. Misery perfusion was not observed by PET in patients without significant expansion (>10 ml), but in 2 of 5 patients with such an expansion. Significant lesion volume expansion occurred in patients with 1) acute hemispheric symptoms and signs, such as consciousness disturbance, conjugate deviation of eyes, mild to severe hemiplegia, and cortical signs, 2) vascular occlusion of the internal carotid or the middle cerebral arteries, either embolic or thrombotic in nature, and 3) small ischemic lesion volume in the initial EP-DWI study. Patients exhibiting these clinical features at early stage of ischemia should be regarded as a high risk group for the lesion volume expansion and they might have a substantially large volume of potentially salvageable tissue.

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Recently, Diffusion weighted imaging (DWI) has been developed to detect early ischemic changes which could not be demonstrated by conventional MR imaging. It is unclear whether a hyperintensity area on DWI shows reversible or irreversible area. To define clinical significance of a hyperintensity area on DWI, we investigate the dependence of a hyperintensity area on both residual cerebral blood flow (CBF) and time from stroke onset.
DWI (5 axial images) using 1.0 T MRI and residual CBF (2 axial images) using 133Xe-SPECT were performed in twenty-eight patients with acute cerebral embolic stroke. The time from stroke onset to DWI was 70-373 min. (mean value of 153.3 min). Cortical hyperintensity area within the middle cerebral artery (MCA) territory was observed in 16 cases (Group I) and not revealed in 12 cases (Group II). Mean CBF in cortical ischemic area within the MCA territory and focal CBF in cortical hyperintensity area within the MCA territory were calculated in each cases. Time from stroke onset to DWI was not significantly different between Group I and II, however, mean CBF in Group I and II (17.3±6.42 ml/100 g/min and 24.4±4.91 ml/100 g/min, respectively) was significantly different (p<0.05). In patients with cortical hyperintensity area, significant linear regression was observed between time (X time.) from stroke onset and focal CBF (Y ml/100 g/min) in cortical hyperintensity area on DWI (Y=0.052X+3.61, p<0.05). Residual CBF in cortical hyperintensity area after three hours from stroke onset was estimated as severe cerebral ischemia as CBF less than 13ml/100 g/min.
These results suggest that cortical hyperintensity area on DWI depends on both residual CBF and time from stroke onset, and indicate irreversible ischemic area. Therefore, in patients with cortical hyperintensity area, thrombolytic therapy should not be considered to avoid hemorrhagic infarction in severe ischemic area.

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Recently, it has been widely reported that thrombolytic therapy could be effective in acute ischemic stroke. We reported relations of cerebral blood flow (CBF) using ¹³³Xe-SPECT and cerebral infarction (CI) on CT/MRI in patients treated with local thrombolytic therapy (LTT).
Thirty-three patients with middle cerebral artery (MCA) stem or trunk occlusion were treated with LTT from 1991 to 1997. The outcome (GOS) of these patients was GR in 26 patients, MD in 2, SD in 4, and Dead in 1. We annalyzed various factors in retrospect view, as follows;
1. NIHSS, Barthel index and modified Rankin scale in day 30th were compared to the grade of immediate recanalization after the treatment by angiography, then, there was no significant difference among them.
2. Pre- and post-treated CBF were evaluated before and after LTT. Mean CBF was measured in anterior and posterior MCA areas without immediate recanalization (28 areas of total 57 areas). Of these 28 non-recanalized area, pre-CBF in areas without CI (n=15) and pre-CBF in areas with CI (n=13) was not significantly different, however, post-CBF in areas without CI (30.3±5.1 ml/100 g/min) was significantly higher than post-CBF in areas with CI (23.3±4.4 ml/100 g/min) (p=0.0008). In areas with increased CBF (postCBF-preCBF≥5ml/100g/min, n=11 areas), CI appeared 2 areas (19%). In areas without increased CBF (postCBF-preCBF<5 ml/100 g/min, n=17 areas), 17 areas (65%) developed CI.
It was suggested that the outcome in patients without immediate recanalization after LTT could be improved by not only improvement of collateral flow but also early recanalization in following period. Conversely, when arterial occlusion was persisted over 8 hours, areas with CBF less than about 27 ml/ 100 g/min could develop CI.

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We have investigated the diffusion-weighted MR imaging (DWI) findings of 40 patients with acute occlusion of internal carotid artery or middle cerebral artery on admission. According to the extent of high intensity areas (HIAs), DWI findings were classified into 4 types, type 1: no detection of HIAs, type 2: detection of HIAs in perforator's territory, type 3: detection of HIAs of limited part of cerebral cortex, type 4: detection of extended HIAs. 4 patients of type 1 were examined within 2 hours after onset. The earliest case with HIA detected by DWI was examined 30 min. after onset. The detection of HIAs on DWI was correlated well to the CBF values obstained by 99m Tc-HMPAO SPECT. HIA was detected exclusive-ly in the hypoperfused area where CBF value was under 20 ml/100 g/min. All 16 patients of type 4 were received conservative therapy, because CBF value on HIAs was very low (0-14 ml/100 g/min.) as irreversible lesions. 14 of 24 patients of type 1-3 underwent revascularization therapy in acute phase and had good results. Some of type 1-3 patients had the indication of revascularization therapy. We concluded that DWI classificasion could be useful for selecting a candidate for revascularization therapy in acute phase.

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The roles and the usefulness of diffusion weighted imaging (DWI) and Xenon Computed Tomography (XeCT) were studied in the cases of major cerebral artery occlusion at the ultra-acute stage. In 12 cases, both DWI and XeCT were examined within 6 hours after onset to decide on the therapeutic strategy. The subjects were 8 males and 4 females, aged 48 to 87 wigh an average age of 70.3). The interval from onset To DWI was from one hour and thiety minutes to five hours and thirty minutes with an average time of three hours. No abnormal findings were found in any of the cases on the routine CT, MRI-T2WI◊FLAIR, while large abnormal findings appeared on the DWI in all the cases. On the XeCT, the decreased cerebral blood flow (CBF) in the ischemic area was shown. This area corresponded to the one showen on DWI. Superselective intraaterial thrombolysis was performed in 5 cases, from which 2 were discharged ambulatorily, 2 wheeling themselves out, and 1 is still bedridden. Conservative therapy was performed in 7 cases. Three followed a good course and had relative good CBFs in the ischemic area. The four cases with poor prognosis of death or being bedridden consisted of the ones with the bilateral lesions, those with an age of over 75 and some complications, or those with the involved area of CBF<10 ml/100 g/min. DWI and XeCT were very useful at the ultra-acute stage of major cerebral artery occlusion because time is extremely important in deciding on the therapeutic strategy including thrombolysis. DWI provided a definite diagnosis in a short time at the ultra-acute stage and XeCT provided the decision of thrombolysis and the prediction of the prognosis.

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Carotid plaque morphology and degree of internal carotid stenosis are mutually dependent factors for the presence of ischemic symptoms and a increased risk of developing subsequent symptoms. We assessed how accurately CT angiography (CTA) can detect carotid plaque morphology referring to intraoperative and histopathological features.
Ten carotid atherosclerotic lesions undergoing carotid endarterectomy (CEA) were imaged on a spiral CT system after a high dose infusion of contrast medium. Axial original images reconstructed with 1 mm image interval, maximum intensity projection (MIP) and multiplanar reconstruction (MPR) images, and volume rendering images for 3-dimensional display were reviewed to assess characteristics of carotid atherosclerotic plaque. All 5 ulcerated plaques identified during CEA and intramural calcification were accurately depicted through MIP processing. Configuration of atherosclerotic fibrous cap, definite differentiation between hard and soft plaques, and detection of intraplaque hemorrhage within atheromatous debris in 1 lesion were feasible with reference to axial original and MPR images. Additionally, 3-dimensional display of carotid plaque using volume rendering was advantageous to surgical planning of CEA.
CTA images can provide useful information for managements of carotid atherosclerotic lesions with respect to plaque surface morphology and plaque composition.

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We have routinely used a newly devised shunt system for 170 carotid endarterectomies (CEAs) Additionally we performed preoperative and intraoperative evaluation of cerebral ischemia during carotid cross-clamping by Matas test and carotid stump pressure and sensory evoked potential. Preoperative and intraoperative studies demonstrated carotid occlusion would produce severe cerebral ischemia in approximately 20%.
The operative mortality and morbidity were 0% and 2.4%, respectively. Perioperatively transient neurological deterioration was observed in 12 cases, and 8 of them were due to ischemia during CEAs. In the follow-up study, 4 of 155 cases showed ischemic attacks, which were not relevant to the operated sites. The 12 cases were dead approximately 5 years on the average after the operation. Their most frequent cause was cancer.
We have demonstrated CEA can be safely performed with a routine application of our shunt system.

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Carotid endarterectomy (CEA) has been established as the standard treatment for high-grade carotid stenosis, and percutaneous angioplasty (PTA) and/or stent replacement (Stent) has been also performed as a new technique. We retrospectively reviewed our experienced 217 cases with 197 CEAsand 28 PTA/ Stents and present postoperative and long-term results. In CEAs, mortality and morbidityrate was 2.5% and one asymptomatic restenosis was identified during follow-up. In PTA/Stents, symptomatic complication was not experienced, but restenosis occurred in more than 50% of cases with PTA. In results, CEAs should be selected as a first choice of surgical treatment in the present conditions. PTAs/Stent may be an alterenative in selective surgical patients, but long-term follow-up is needed to determine the ulitimate durability.

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We report excellent initial results of stenting for stenosis of major cerebral arteries experienced between April 1997 and June 1998. Patients ranged in age from 61 to 78 year old (mean 65 year old). The location of the lesion included cervical carotid artery: 10, orifice of vertebral artery: 3, subclavian artery: 3. All lesion were high grade more than 60%. Ten were symptomatic (TIA 5, minor stroke 1, VBI 2. others 2), and six were asymptomatic. Stents utilized were Palmaz stents, the balloon expandable type originally developed for peripheral arteries. Stents were placed at the lesion after predilatation in some patients and primarily in other patients. Almost complete dilatation was obtained in every patient without any permanent adverse event. Bradycardia and mild hypotension due to vaso-vagal reflex was observed in two patients with carotid stenosis until next day after treatment. TIA was experienced in two patients with carotid stenosis. No further ischemic events were observed during the short-term follow-up period. Usefulness of stenting for major cerebral artery stenosis was indicated by our initial results. Stenting will play an important role in the treatment of cerebrovascular disease in the near future, though the development of better stents for the cerebral arteries and long-term follow-up are mandatory.

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The study of the structure of atherosclerotic cartoid plaques has its place in the explanation of the onset of neurologic symptoms. In order to investigate possible relationships between carotid plaque morphology and clinical events, 121 endarterectomy specimens were studied clinicopathologically. Each specimen was examined for gross and histopathological features.
The following plaque characteristics were present: ulcer formation (63 plaques, 52.1%), intraplaque hemorrhage (57 plaques, 47.1%) and fresh thrombi (32 plaques, 25.6%). All three findings were closely correlated with the presence of symptoms. Hypertension and hypercholesterolemia did not significantly correlate with plaque characteristics. Diagetes militias had strong correlations with plaque characteristics, especially intraplaque hemorrhage.

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Surgical outcome of 905 ruptured intracranial aneurysms were retrospectively analyzed in relation to presurgical Hunt and Kosnik's clinical grade, location of aneurysm, timing of surgery and patient's age. Causes of poor outcome were also analyzed in the cases with unfavorable outcome. Seven hundred nine cases had good outcome and 196 cases had poor. Presurgical poor grade resulted in unfavorable outcome; about one third of grade III and two thirds of grade IV had poor outcome. Cases who underwent early surgery tended to have poor outcome, because of more cases with poor clinical grade. Aged patients had worse result, because of poorer grade and of worse result in grade I, II and III than young patients. In 196 cases with poor surgical result, primary brain damage (PBD) was the most often (45.9%) cause of poor outcome, and vasospasm (VS) was the second (28.1%). PBD was the major cause of poor result in grade IV and V; VS was so in grade II and III. In vertebrobasilar aneurysms brain damage from surgical procedure sometimes resulted in poor outcome. Early surgery and enough treatment for vasospasm are recommended for ruptured aneurysms. Surgical outcome of elderly patients and cases with poor presurgical clinical condition should be improved.

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A retrospective analysis has been investigated about the optimal perioperative management of 200 consective subarachnoid hemorrhage (SAH) patients admitted to the Advanced Critical Care Emergency Center of Nippon Medical School in recent two years. 82 cases were males and 118 cases were females. Of the 200 patients, 130 were in poor grade (grade IV and V) including 27 patients in cardiopulmonary arrest (CPA) condition. 89% of the patients were group 3 and 4 according to Fisher CT classification. The algorithm in the acute management of SAH can be classified into prehospital phase and hospital phase. The hospital phase can be further classified into resuscitative phase, diagnostic phase, operative phase and postoperative neurointensive care phase. Of 21 patients with rebleeding, 6 cases were in prehospital phase and 6 cases were in diagnostic phase. Based on these findings, in prehospital phase strict control of blood pressure and sedation is recommended during transfer. Three dimentional CT angiography is less invasive and very useful in the perioperative management of SAH. The introduction of endovascular occlusion with GDC coil and brain hypothermial treatment will have the possibility of improving the overall prognosis of severe SAH.

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Pathophysiology of severe subarachnoid hemorrhage (SAH) is still unclear. Neurological grading of SAH, such as WFNS grading, is popularly employed to select patients with severe SAH for radical surgery. Although the cases of whom grade improve after admission are often encountered, preoperative sedation or barbiturate and/or hypothermia therapy mask the improvement of neurological grade. These let us to analyze natural course of WFNS grade of patients with severe SAH and the outcome.
Forty-four patients with WFNS grade IV-V on admission were enrolled in this study. The patients received mannitol and/or ventricular drainage, were observed without neuroleptics or analgesics for 12 hours under control of blood pressure, and the then WFNS grade was re-evaluated. When the patients showed grade III or better, radical surgery was performed.
90% of patients with grade IV on admission showed III or better 12 hours after admission, and received radical surgery. However, less than half of patients with grade V on admission showed IV or better, and only 30% of them received radical surgery. Over 80% of patients received radical surgery showed good prognosis. These results suggest that WFNS grade after 12 hours observation may help to determine the indication of radical surgery for severe SAH.

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We evaluated surgical results for patients with poor-grade subarachnoid hemorrhage (SAH) with packed intraventricular hemorrhage (IVH) due to aneurysmal rupture.
We performed early surgery within 24 hr after onset in 74 patients with poor-grade (World Federation of Neurological Surgeons grade 4 and 5) SAH without intracerebral hemorrhage. In patients with packed IVH, we extensively evacuated intraventricular clots via frontal corticotomy under microscopy.
Overall, 42% of the patients with poor-grade SAH (74 cases) who underwent craniotomy in the acute stage had facorable outcome, and mortality rate was 30%. By multivariate analysis, variables significantly related to favorable outcome in patients with poor-grade SAH included the absence of a packed intraventricular clot on CT scan, the absence of past history of cardiac disease, and a Glasgow coma scale score of 11 or 12. Among 18 patients with packed IVH, no patient had a favorable outcome, and 7 died.
Packed IVH predicts a very poor outcome in patients with poor-grade SAH despite direct clot evacuation. We speculated that an intraventricular mass caused by packed IVH consisting of massive clots easily causes direct compression and destruction of the paraventricular structures.

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Favorable timing of aneurysmal surgery for aged group (≥70 year-old, group A) and non-aged group (≥70 year-old, group B) were evaluated on 1789 patients who were admitted within 48 hours after subarachnoid hemorrhage (SAH) and in which cerebral aneurysms were verified with angiogram. Late surgery (day 11 or later) showed significantly favorable results compared to early surgery (within day 3) in all grades of SAH (Hunt and Hess classification) in group B and in good grade (I, II) in group A. Patients with late rebleeding (day 4 or later) before surgery and patients who did not undergo surgery because of vasospasm or initial damage were added to a group of late surgery and they were defined as a late management group. In group B, early surgery revealed higher incidence of favorable outcome than late management in grade I-IV. In group A, late management showed better result in good-risk group (grade I, II), whereas early surgery yielded the significantly higher incidence of favorable outcome than late management in poor-risk patients (grade IV). These results suggest that early surgery is recommended for aneurysmal surgery in non-aged patients regardless of severity. It is also indicated that for aged group, late surgery on good-risk patients and early surgery on poor-risk aged result in better outcome.

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Since the development of endovascular treatment, mangement of intracranial aneurysms has been changing. There are several merits and demerits in either mode of treatment. However, in cases of ruptured aneurysms, subarachnoid hemorrhage itself makes the patient's condition critical and not due to the existence of aneurysms.
Retrospective study of 437 cases of cerebral aneurysms including 345 SAH cases over 4 years period has been reported. Out of 345 cases, surgical clipping was performed in 254 cases and endovascular treatment was done in 26 cases. No treatment was performed in 65 cases. In direct surgical treatment group, morality rate was 9.8% and good recovery was seen in 75% of cases. In endovascular intervention group morality rate was 42.3% mainly because of severity of their neurological grading and older age. Six out of 26 cases had complications such as leakage of contrast medium (ruptured) in 4 cases, embolic infarction 2 cases. We have discussed which type of treatment suitable for the aneurysm cases, considering permanent cure.

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We performed multimodal treatment mainly using mild hypothermia therapy for patients with poor-grade subarachnoid hemorrhage induced by ruptured cerebral aneurysm. Clipping was performed in combination with mild hypothermia therapy for patients presenting with bilateral pupillary dilatation and loss of light reflex as a results of formation of a large temporal hematoma due to aneurysmal rupture. Such patients have peviously been considered hard to save their livers, but we could obtain good outcomes. Cerebral vasospasm was managed by percutaneous transluminal angioplasty and intraarterial infusion of papaverine under mild hypothermia therapy, which resulted in good improvement of CBF. On the other hand, we performed mild hypothermia therapy for those patients who showed no improvements of their neurological manifestations in response to intra-arterial infusion of papaverine.
Some of these patients showed good improvement after re-warming although their CBF reached a critical level during mild hypothermia therapy, and could walk by themselves at discharge. Meanwhile, however, in other patients mild hypothermia therapy failed to prevent the progress of cerebral vasospasm, and re-warming resulted in worsening of the vasospasm. Further clinical studies in this regard are rern irefl.

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Effect of argatroban on neurological symptoms and activities of daily living (ADL) was evaluated in 68 acute cerebral thrombosis patients. Disturbance of consciousness and nurological symptoms improved significantly as a result of treatment with argatroban. ADL evaluated using the Barthel Index improved significantly from day 3 of treatment.
Stratified analysis of ADL was conducted with respect to infarct region, time of starting treatment after onset, and types of cerebral thrombosis. For infarcts in the territory of deep perforators, ADL improved significantly from day 3 of treatment regardless of whether treatment started within 12 hours or more than 12 hours after onset. Cortical infarction improved significantly only when treatment started within 12 hours after onset. Both of lacunar and atherothrombotic infarction improved significantly from day 7 of treatment. The evaluation suggested that argatroban is useful for the treatment of acute cerebral thrombosis. In the case of cortical infarction, which results in severe ischemia and rapidly progresses from ischemic penumbra to infarction, it is important to start treatment with argatroban as soon as cerebral thrombosis is diagnosed.

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We compared the improved ratio of neurological symptoms in cerebral thrombosis in regard to clinical category and drug. The group which we administrated ozagrel Na for the lacunar infarction and argatroban for the atherothrombotic infarction was higher recovery in neurological symptoms than the group which we administrated argatroban for the lacunar infarction and ozagrel Na for the atherothrombotic infarction. In result, it was important to select drug matched with clinical category.
In the cases of argatroban, it was not significant difference between the improved ratio of clinical symptoms for the lacunar infarction and that for the atherothrombotic infarction, argatroban was effective for not only the atherothrombotic infarction but also the lacunar infarction. On the other hand, in the cases of ozagrel Na, the improved ratio for the lacunar infarction was significantly different from that for the atherothrombotic infarction, ozagrel Na was not effective for the atherothrombotic infarction.

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A randomized, double-blind, placebo-controlled clinical trial of ebselen, a seleno-organic compound with anti-oxidant activity, was conducted in patients with acute ischemic stroke. Ebselen or placebo granules suspended in water (150mg b.i.d.) was orally administered within 48 hours of onset, and was continued for 2 weeks. Major end points were the outcome of patients at 1 month and 3 months after the start of treatment. The modified Mathew Scale and modified Barthel Index scores at 1 and 3 months were also studied as secondary outcome measures. Three hundred and two patients were enrolled in the trial. Both intent-to-treat anaylsis of 300 patients (151 given ebselen and 149 given placebo) and protocol-compatible analysis of 242 patients (118 given evselen and 124 given placebo) revealed that ebselen treatment achieved a significantly better outcome than placebo at 1 and 3 months, respectively. The improvement was particularly significant in patients with cortical artery infarcts and who received ebselen therapy within 24 hours of onset. There was a corresponding improvement in the modified Mathew Scale and modified Barthel Index scores. These findings suggest that ebselen may be a promising neuroprotective agent in the acute stroke.

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Nonvalvular atrial fibrillation (NVAF) is emphasized as a cause of cardioembolic stroke. However little has been investigated about the role of early anticoagulation for preventing early recurrence in elderly cardioembolic stroke patients with NVAF. Here we present the results of early anticoagulation therapy using low-dose heparin in elderly patients with cardioembolic stroke and NVAF, and compare them retrospectively with the rates of recurrence and hemorrhagic accident in untreated patients. Forty-one elderly patients who were admitted to our hospital from July 1992 to May 1998 with NVAF were treated with low-dose heparin (5000 IU/day) immediately after cardioembolic stroke (H+ group, mean age; 84.9). Only one patient (2.4%) suffered recurrent embolism, and 11 patients (26.8%) showed hemorrhagic infarction on CT within 28 days after the initial stroke. Severe hemorrhagic complications were not observed. In a control group (H - group, mean age; 80. 1), who were admitted to our hospital from July 1986 to July 1992 and treated only with conservative therapy, recurrent embolic stroke occurred in 6 (16.2%) of 37 patients, and hemorrhagic infarction was found in 15 (40.5%). Significantly fewer patients suffered recurrent embolism in the H + group than in the H - group (p<0.05). There was no significant different in the occurrence of hemorrhagic infarction between the two groups. We conclude that acute anticoagulation using low-dose heparin is employed safely, and prevent recurrent embolism during the acute phase in most elderly patients.

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We studied 33 patients with thromboembolic stroke in carotid territory treated with superselective intra-arterial fibrinolysis with aspecial attention to collateral flows and residual cerebral blood flow (CBF). Patients were divided into four subgroups by the location of thromboembolus. Group M2 with occlusion at M2 or more distal portion of the middle cerbral artery (MCA) contained 13 patients. Group MI-D with occlusion at distal M1 portion of MCA, without ischemia of perforators' area of MCA, comprised 9 patients. Group M1-P with occlusion at proximal M1, with ischemia of perforators' area, consisted of 8 patients. Group IC with occlusion at the intracranial internal carotid artery contained 4 patients. Collateral flows and residual CBF were evaluated by angiography, dynamic CT and SPECT.
100% of patients in Group M2 and 78% of Group MI-D had favorable outcome. However, 57% in Group M1-P and 50% in GroupIC were unfavorable, especially 43% in the former and 25% in the latter died because of hemorrhagic transformation. The evaluations of angiography, dynamic CT and SPECT showed poor collateral flows and residual CBF in all unfavorable patients.
We conclude that locations of thromboembolus, collateral flows and residual CBF, as well as the time from onset, are very important factors in indication for acute fibrinolytic therapy in thromboembolic stroke in carotid territory.

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We have examined the effects of a novel anti-P-selectin antibody on ischemic brain injury after 24 hr of permanent middle cerebral artery occlusion (MCAO) in rat. Male Wistar rats were subjected to MCAO by an insertion of a silicone rubber cylinder for 24 hr. Anti-rat P-selectin monoclonal antibody, ARP 2-4, was injected intravenously at a dose of 1 mg/kg at 5 min before the induction of MCAO. Regional cerebral blood flow (rCBF) was measured just after and at 8 hr of MCAO. After decapitation of rats at 24 hr of permanent MCAO, infarct size was compared between the antibody and vehicle treated group. In addition, immunohistochemistry for leukocyte infiltration and HSP72, and histochemistry for TUNEL were also compared. Pretreatment with ARP 2-4 improved rCBF at 8 hr of MCAO (55.4 ± 11.7% of control, n=5) as compared to vehicle group (24.2 ± 11.8%, n=5, p<0.02). Although leukocyte infiltration was not normally detected by monoclonal antibodies for CD11a and CD18, it became remarkably evident at 1 day of MCAO. Treatment with ARP 2-4 significantly reduced the numbers of leukocyte, infarct size, neurons with positive HSP72 and TUNEL stainings. These data suggest an important role of P-selectin in ischemic brain damage, and a future therapeutic potential to human stroke patients.

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VEGF plays a pivotal role in angiogenesis in vivo, and also increases vascular permeability which might exacerbate ischemic brain edema. We here investigated the effect of this factor on the brain after transient ischemia in terms of infarct volume and edema formation, as well as cellular injury.
After 90 min of transient MCA occlusion, VEGF (1.0 ng/μl, 9 μl) was topically applied on the surface of the reperfused rat brain. A significant reduction of infarct volume was found in animals with VEGF application at 24 h or reperfusion as compared to cases with vehicle treatment. Brain edema was also reduced in VEGF treatment animals, and furthermore, extravasation of evans blue was also decreased in those animals. TUNEL and immunohistochemical analysis for HSP72 showed an amelioration of the stainings at 24 and 48 h after reperfusion with VEGF treatment, which indicated reduction of neuronal damage.
These results indicate that treatment with topical VEGF application significantly reduces ischemic brain damage such as infarct volume, edema formation, and extravasation of EB, and that the reduction: were associated with that of neuronal injury.

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Oxygen radicals, produced in mitochondria, are implicated in the pathogenesis of ischemic brain injury. We determined the role of manganese-superoxide dismutase (Mn-SOD) in cerebral ischemia, using mutant mice with decreased activity of Mn-SOD (Sod2 -/+). Sod2 -/+ and its littermate wild type mice were subjected to permanent middle cerebral artery occlusion. Mitochondrial viability assay demonstrated accelerated development of mitochondrail injury in Sod2 -/+. Sod2 -/+ showed advanced neurological deficits and exacerbated infarct size without altering DNA fragmentation induction. The present study suggests that mitochondrial susceptibility to oxidative stress induces mitochondrial impairment causing energy failure, and results in exacerbation of ischemic brain injury through necrotic pathway.

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Recently hypoxic tolerance by chemical preconditioning with the neurotoxin 3-nitropropionic acid (3-NPA), chemical inhibition of oxidative phosphorylation, was reported in rats. In this study, we determined the subclinical dose in gerbils intoxicated with 3-NPA (experiment-1) and investigated whether the tolerance phenomenon similar to chemical preconditioning in rats against hypoxia can be observed in gerbil hippocampal slices (experiment-2). At 3 hours prior to slice preparation, experimental animals were given a single intraperitoneal injection of 3-NPA at a dose of 4 mg/kg which was determined by clinical signs and morphological findings in 3-NPA-intoxicated gerbils in experiment-1. An in vitro gerbil hippocampal slice model was used to study the delay to hypoxic depolarization (HD) during hypoxia and the recovery of field excitatory postsynapic potential (fEPSP) after hypoxia. The delay to HD during hypoxia was significantly prolonged in preconditioned group (203.2 ± 78.0 sec; mean ± SD) compared to control group (84.5 ± 34.4 sec) (p<0.001). The recovery of fEPSP after a fixed period of hypoxia (8 min) was better improved in the preconditioned slices (80.9 ± 33. 1%) than in control slices (23.2 ± 15.3%) (p<0.001). These findings indicate that chemical preconditioning with 3-NPA induces early-onset tolerance against hypoxic damage to gerbil hippocampus due to proloning the delay to HD.

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FK506 is an immunosuppressant widely used in liver, kidney and bone marrow transplantation. Recently, some authors have reported on the neuroprotective properties of FK506 in vitro and in vivo, but the cellular mechanisms underlying the neuroprotective action it exercises in experimental stroke remains uncertain.
In former reports, we have already demonstrated that intravenous injection of FK506 (0.3 mg/kg) reduces the ischemic cortical damage when administered immediately after transient middle cerebral artery occlusion (MCAO). The present study invistigates the therapeutic time window for FK506 in transient focal ischemia in rats. The left MCAO were occluded for 2h by intraluminal suture and reperfused for 24h. FK506 reduced the cortical infarction volume by 44% and 45%, when administrated 30 min and 60 min after the onset of ischemia, but had no neuroprotective activity when administrated 120 min after ischemia. This effect is unlikely to be due to the reduction of brain edema, since there was no difference in edema in FK506 treated and vehicle treated groups. These results suggest the therapeutic time window for FK506 administrated intravenously is between 60 min and 120 min, because of efficacy to ameliorate neuronal damage at 60 min but not at 120 min, and that FK506 is a novel candidate for clinical application for ischemic stroke, and is likely to be more effective with less side-effects than present medical strategies for ischemic stroke in human.

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Upon experimental cerebral infarction of rats midkine (MK) is expressed 1 to 4 days after the onset of infarction at the surrounding zone of the infarct. We examined the effect of intraventricular administration of MK to mongolian gerbils on the hippocumpal delayed neuronal death of CA-1. The yeast producing MK was injected into the ventricle. Thereafter, the bilateral common arteries were occluded for 5 min. The animals were sacrificed 7 days after th ischemic insult. The coronal 5 μm-thick sections for hematoxylin-eosin staining included the hippocampal area at 1.4-1.8 mm posterior to bregma. Hippocampal nuclear number was 272 ± 44/mm in sham operated group (n= 13, mean ± S.D.), 10 ± 10/ mm in vehicle administration group (n=11), 236 ± 40/mm in 2, ug administration group (n=4), 222 ± 11/ mm in 1 μg group (n=5), 232 ± 18/mm in 0.5 beg group (n=4), and 50 ± 91/mm in 0.25 pg group (n=6). A significant F ratio was found in one-way analysis of varience, then post-hoc Fisher's protected least significant differences test was performed, which showed the significances in the administration groups of 2, 1, and 0.5 ug (p<0.0001), and 0.25 ug (p<0.5). This results indicated small amount of MK protein had neurotrophic activity in the inhibition of hippocampal delayed neuronal death.

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